Airways inflammation is thought to play a central role in the pathogenesis of asthma. However, the precise role that individual inflammatory cells and mediators play in the development of airways hyperreactivity and the morphological changes of the lung during allergic pulmonary inflammation is unknown. In this investigation we have used a mouse model of allergic pulmonary inflammation and interleukin (IL) 5-deficient mice to establish the essential role of this cytokine and eosinophils in the initiation of aeroallergen-induced lung damage and the development of airways hyperreactivity. Sensitization and aerosol challenge of mice with ovalbumin results in airways eosinophilia and extensive lung damage analogous to that seen in asthma. Aeroallergen-challenged mice also display airways hyperreactivity to beta-methacholine. In IL-5-deficient mice, the eosinophilia, lung damage, and airways hyperreactivity normally resulting from aeroallergen challenge were abolished. Reconstitution of IL-5 production with recombinant vaccinia viruses engineered to express this factor completely restored aeroallergen-induced eosinophilia and airways dysfunction. These results indicate that IL-5 and eosinophils are central mediators in the pathogenesis of allergic lung disease.

/pdf/interleukin-5-deficiency-abolishes-eosinophilia-airways-2tadb7e4r5.pdf

Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.

Inflammatory mediators of asthma: an update.

Traditionally, steroid hormone action has been described as the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid action has been widely recognized only recently. Evidence for these rapid effects is available for steroids of all clones and for a multitude of species and tissues. Examples of nongenomic steroid action include rapid aldosterone effects in lymphocytes and vascular smooth muscle cells, vitamin D3 effects in epithelial cells, progesterone action in human sperm, neurosteroid effects on neuronal function, and vascular effects of estrogens. Mechanisms of action are being studied with regard to signal perception and transduction, and researchers have developed a patchy sketch of a membrane receptor-second messenger cascade similar to those involved in catecholamine and peptide hormone action. Many of these effects appear to involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C, and tyrosine kinases. The physiological and pathophysiological relevance of these effects is unclear, but rapid steroid effects on cardiovascular, central nervous, and reproductive functions may occur in vivo. The cloning of the cDNA for the first membrane receptor for steroids should be achieved in the near future, and the physiological and clinical relevance of these rapid steroid effects can then be established.

Specific, nongenomic actions of steroid hormones

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.

The airway inflammation underlying asthma is regulated by a network of mutually interacting cytokines. The exact functional role of each individual cytokine in the pathogenesis of the disease remains to be fully established. Type 2 T-helper cells are currently considered to play a crucial role in this process. In vivo animal data suggest a sequential involvement of interleukin (IL)-4 and IL-5 in the induction of allergen-induced airway changes. The potential role of other type 2 T-helper cell-like cytokines in asthma is increasingly being recognized. In particular, IL-4 and -13 display a large degree of redundancy. Whereas IL-4 seems to be crucial in the primary allergen sensitization process, IL-13 might be more important during secondary exposure to aerosolized allergen. Animal models also indicate that T-cell-derived cytokine production, rather than eosinophil influx or immunoglobulin-E synthesis, is causally related to altered airway behaviour. An important aspect when evaluating the functional role of cytokines in a complex disease such as asthma is the interaction with other cytokines in the microenvironment. Increased expression of pro-inflammatory cytokines such as tumour necrosis factor-alpha can further enhance the inflammatory process, and is increasingly linked to disease severity. In addition, decreased expression of immunoregulatory cytokines, including interleukin-12, interleukin-18 or interferon gamma could also strengthen the type 2 T-helper cell-driven inflammatory process.

https://erj.ersjournals.com/content/erj/18/34_suppl/24s.full.pdf

Cytokines in asthma

Effect of Anti-IL-5 Monoclonal Antibody on Allergic Bronchial Eosinophilia and Airway Hyperresponsiveness in Mice.

1 An intratracheal injection of murine recombinant interleukin 5 (mrIL‐5, 2–15 μg/0.25 ml/animal) induced a dose‐dependent increase in the number of macrophages, eosinophils, neutrophils and epithelial cells in the bronchoalveolar lavage fluid (BALF) of guinea‐pigs 24 h after administration. Bovine serum albumin (15 μg/0.25 ml/animal), used as a reference material, did not cause any change of this type. 2 The intratracheal administration of mrIL‐5 at a dose of 15 μg showed a tendency to increase the number of these pulmonary inflammatory cells and epithelial cells in the BALF at 12 h with a significant increase observed at 24 h. 3 Prednisolone (20 mg kg−1, i.p.) inhibited the mrIL‐5‐induced increase in macrophages, eosinophils, neutrophils and epithelial cells. Ketotifen (2 mg kg−1, i.p.) reduced the mrIL‐5‐induced increase in the eosinophil, neutrophil and epithelial cell populations. The simultaneous injection of 2% disodium cromoglycate (DSCG) into the trachea prevented the mrIL‐5‐induced increase in the number of airway epithelial cells, without affecting changes in the other inflammatory leukocytes. 4 These results suggest that mrIL‐5 is a potent inducer of lung inflammation, in terms of increased inflammatory leukocytes and epithelial cells in guinea‐pig BALF. Prednisolone, DSCG and ketotifen are effective against mrIL‐5‐induced pulmonary inflammation, especially the desquamation of bronchial epithelial cells.

Effect of Murine Recombinant Interleukin-5 on the Cell Population in Guinea-Pig Airways.

We have reported that an intratracheal injection of murine recombinant interleukin‐5 (mrIL‐5, 15 μg/0.0 ml/animal) induces the increased number of inflammatory leucocytes and epithelial cells in bronchoaiveolar lavage fluid (BALF) 24 hr after administration of mrIL‐5 in guinea‐pigs [1]. In this paper, we have examined the effects of mrIL‐5 on bronchial reactivity in guinea‐pigs. An intratracheal injection of mrIL‐5 (15 μg/0.0 ml/animal) induced airway hyperresponsiveness to acetytcholine (ACh) which was accompanied with eosinophilia and neutrophilia in blood at 24 hr in guinea‐pigs. Bovine serum albumin (BSA, 15 μg/0.0 ml/animal) used as a reference material did not cause airway hyperresponsiveness, blood eosinophilia and neutrophilia. Prednisotone (20 mg/kg, i.p.) inhibited mrIL‐5‐induccd airway hyperresponsiveness, eosinophilia and neutrophilia. Ketotifen (2 mg/kg, i.p.) also reduced this airway hyperresponsiveness and neutrophilia but not eosinophilia. In contrast, the injection of 2% disodium cromoglycale (DSCG) into the trachea showed the tendency of inhibitory effects against mrIL‐5‐induced airway hyperresponsiveness, eosinophilia and neutrophilia. The present data indicate that mrIL‐5 induces airway hyperresponsiveness, blood eosinophilia and neutrophilia in guinea‐pigs and that prednisolone and ketotifen inhibit mrIL‐5‐induced airway hyperresponsiveness accompanied with reduction of the increased number of leucocytes, suggesting that eosinophils and neutrophilia in blood may be important for the onset of bronchial hyperresponsiveness caused by mrIL‐5 in guinea‐pigs.

Effect of Murine Recombinant Interleukin-5 on Bronchial Reactivity in Guinea-Pigs.

We previously reported that Wen-Qing-Yin (Unsei-in), a traditional Chinese blended medicine, inhibited the induction phase of various kinds of delayed type hypersensitivity (DTH) and local graft-versus-host (GvH) reactions, but did not affect humoral immune responses or the effector phase of DTH in experimental animals. In another report, we demonstrated that Phellodendri Cortex (bark of Phellodendron amurense Rupr. Rutaceae) was a component having the most potent suppressive effect on the cellular immune response among the 8 medical plants composing Unsei-in. In the present study, we isolated OB-1 and OB-5 from Phellodendri Cortex as the biologically active principles to suppress local GvH reactions in mice. OB-1 and OB-5 are quaternary base alkaloids known as magnoflorine and phellodendrine, respectively. They suppressed the local GvH reaction, when given i.p. to the host mice at 5-20 mg/kg for 8 consecutive days from the day of spleen cell transfer to cause the reaction. Both OB-1 and OB-5 suppressed picryl chloride-induced delayed type hypersensitivity (PC-DTH) when given i.p. to mice at 10 and 20 mg/kg for 5 consecutive days from the day of the sensitization, but did not suppress it when given at the time of the challenge. These results suggest that OB-1 and OB-5 suppress the induction phase but not the effector phase of the cellular immune response. They are expected to have a value as a new type of immunosuppressor.

Principle of the bark of Phellodendron amurense to suppress the cellular immune response.

Passive cutaneous anaphylaxis (PCA) was elicited both in the ear and in the dorsal skin of 13 strains of mice at the same time and assessed quantitatively by measuring the amount of extravasated dye. Body pigments of colored mice such as DBA/2 (chocolate), C3H/He (brown) and C57BL/6 (black) did not interfere with the measurement of dye. In the ear response, ICR was a higher responder, C57BL/6 and BALB/c-nu/nu were lower responder strains. In the dorsal skin response, however, ICR was a lower responder, BALB/c-nu/nu, Hairless and WBB6F1-+/+ were higher responders. WBB6 F1-W/Wv was a nonresponder in both responses. The ear response was highly reproducible and the dorsal skin response of each strain was 1/2-1/10 of its ear response except for BALB/c-nu/nu. The PCA bluing regions on the dorsal skin of BALB/c-nu/nu were clearly delineated and the response was almost comparable to its ear response.

Homologous Passive Cutaneous Anaphylaxis in Various Strains of Mice.

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